Colorectal cancer remains one of the leading causes of cancer-related deaths in the United States and abroad. In 2007, 142,672 people were diagnosed with colorectal cancer in the United States and 53,219 people died. While much has been learned recently in regards to how colorectal cancer works at the molecular level, clinicians still rely on therapeutic treatments such as surgery, radiation and chemotherapy. Early diagnosis, made possible by advances in imaging technology and molecular diagnostics are factors that greatly enhance the success of any treatment. Although the efficacy of all these treatments has improved over the years, the improvement in cure rates and the increase in longevity have been incremental. Even the new targeted therapies resulting from the revolution in molecular oncology have, for the most part, improved outcomes only modestly.
Two of the most challenging aspects of managing colorectal cancer patients are metastasis and recurrence. Metastasis occurs when the colorectal cancer spreads to distant organs from the primary tumor. While it is often possible to respect the primary tumor, it is the metastasis that frequently ends up killing the patient because they become too numerous or entwined with healthy host tissue to treat surgically. According to the American Cancer Society, the five year survival rate in the United States for patients diagnosed with Stage IIIC colon cancer between 1998 and 2000 was 28%, which dropped to only 6% at Stage IV (i.e., metastatic colorectal cancer).
Recurrence is the phenomenon by which colorectal cancer returns after initially responding to treatment and apparently disappearing. Apart from the emotional toll inflicted on patients and their families, recurrence is problematic because the returning cancer may be less responsive to the therapy or therapies that were effective to fight the first cancer. For other patients, prior treatments for the first cancer may have caused irreversible side effects, such as cardiac or neurological damage. In such patients, the risks of using the same therapy to fight the recurrent cancer may be too great. Under these circumstances, a patient may have fewer treatment options with a concomitantly greater risk of mortality.
While improvements in radiation treatment, chemotherapy and the advent of targeted therapies have increased the longevity of patients stricken by colorectal cancer, many such patients continue to die within months to a few years after their diagnosis. An urgent need therefore exists for new treatments effective against metastatic colorectal cancer and recurrence colorectal cancer. In similar manner, the need to prevent development of non-malignant polyps and adenomas into malignant tumors using chemoprevention exists.
Acetylsalicylic acid, also known as “Aspirin,” was discovered by the German chemist Felix Hoffmann in 1897. (See FIG. 1.) Aspirin is considered a “pro-drug” that is hydrolyzed into salicylate and acetyl upon cellular absorption. Salicylate is known to inhibit the COX enzyme and augment fatty acid oxidation through the Adenosine Monophosphate Protein Kinase (AMPK) enzyme.
Aspirin's initial intended therapeutic use was as an anti-inflammatory agent. After decades of pharmacologic use, a number of other properties attributable to aspirin have emerged. These include anti-coagulant, anti-pyretic, and analgesic properties. In recent years, new clinical evidence has emerged supporting aspirin's ability to reduce cancer development and metastasis. However, for the anti-cancer properties of aspirin to become significant, an extended period of use is required at a relatively high pharmacologic dose (approximately 600 mg). It is known that high levels of aspirin may lead to undesired gastrointestinal side effects.
Aspirin is classified as a non-steroidal anti-inflammatory, or “NSAID”. This classification of compositions includes salicylic acid, aspirin, ibuprofen, and valdecoxib. Salsalate, as shown in FIG. 2, is an aspirin homolog that undergoes a similar metabolic fate as aspirin, however salsalate hydrolyzes into two salicylates. As shown in FIG. 3, the structure of valdecoxib is structurally different from salicylic acid, aspirin and ibuprofen. It is known in the art that valdecoxib is extremely toxic in humans.
Fish oil consumption has been linked to human health benefits. Fish oil is comprised of triglycerides that are rich in Long Chain Poly Unsaturated Fatty Acids (LC-PUFAs). Docosahexaenoic acid (DHA) and Eicosapentaenoic Acid (EPA) are common omega-3 fatty acids found in fish oil. A number of studies have shown that DHA possesses anti-inflammatory properties, enhances neuronal growth and induces apoptosis of cancer cells. The benefits of fish oil consumption are partly attributable to its high content of DHA. Ethyl ester versions of DHA and EPA are currently being used for the treatment of hyperlipidemia.
The structures of DHA and AA (Arachidonic Acid), as shown in FIG. 5, show that DHA and AA are poly unsaturated omega-3 and omega-6 fatty acids, having 22 and 20 carbons respectively. The high level of unsaturation of DHA and AA is believed to play a beneficial role in plasma membrane fluidity. Furthermore, the high level of unsaturation makes DHA and AA highly reactive during oxidative stress. Metabolites of DHA, such as resolvins and electrophilic oxo derivatives (EFOXs) have been shown to be potent anti-inflammatory mediators. The high reactivity of DHA and AA is kept under control by incorporating it into triglycerides and thus controlling its intracellular bioavailability. It is well known that LCPUFA supplementation results in plasma membrane enrichment, which can modulate physiological processes relating to cellular apoptosis.
The salicylic acid component of the conjugate has well documented anti-cancer and anti-metastatic properties. Therefore, the molecule can be used in cancer therapy to inhibit cellular division of cancerous cells and prevent metastasis. Equally effective is the pro-apoptotic effect of the fatty acid moiety.
Recent clinical studies provide evidence to support aspirin's anti-cancer and anti-metastatic properties. However, these studies have shown a measurable benefit only after extended periods of use and at high pharmacologic doses. Furthermore, free poly unsaturated fatty acids have a short half life before being converted to triglycerides and entering circulation. Therefore, a need in the art exists to overcome the insufficiencies of known treatments. The proposed formulations will allow a synergistic pro-apoptotic effect superior to the separate, individual molecules that comprise the proposed formulations. The required pharmacological dose and the variable intracellular concentrations of aspirin and fatty acids with respect to time and cell type can be achieved optimally using the inventive compositions, which may be referred throughout the specification as “Lipospirs” or fatty acid/salicylate conjugates. The conjugate allows for concurrent intracellular delivery of two drugs that when present in the cell can synergize and augment the anti-cancer properties of free fatty acids and salicylates.